Structure of human Fe–S assembly subcomplex reveals unexpected cysteine desulfurase architecture and acyl-ACP–ISD11 interactions
作者： Seth A. Cory , Jonathan G. Van Vranken , Edward J. Brignole , Shachin Patra , Dennis R. Winge
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摘要: In eukaryotes, sulfur is mobilized for incorporation into multiple biosynthetic pathways by a cysteine desulfurase complex that consists of catalytic subunit (NFS1), LYR protein (ISD11), and acyl carrier (ACP). This NFS1–ISD11–ACP (SDA) forms the core iron–sulfur (Fe–S) assembly associates with proteins ISCU2, frataxin (FXN), ferredoxin to synthesize Fe–S clusters. Here we present crystallographic electron microscopic structures SDA coupled enzyme kinetic cell-based studies provide structure-function properties mitochondrial desulfurase. Unlike prokaryotic desulfurases, structure adopts an unexpected architecture in which pair ISD11 subunits form dimeric complex, clarifies critical role eukaryotic assemblies. The different quaternary results incompletely formed substrate channel solvent-exposed pyridoxal 5′-phosphate cofactor provides rationale allosteric activator function FXN systems. also reveals 4′-phosphopantetheine–conjugated acyl-group ACP occupies hydrophobic ISD11, explaining basis stabilization. framework understanding interactions acceptor sulfur-containing pathways, elucidating mechanistic details cluster biosynthesis, clarifying how defects lead diseases such as Friedreich’s ataxia. Moreover, our support lock-and-key model associate acyl-ACP mechanism fatty acid biosynthesis coordinate expression, maturation, activity respiratory complexes.
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